P-nu, nu-di-(2-chloroethyl)-aminophenoxyalkanoic acids and alkyl esters thereof



United States Patent This invention relates to chemotherapeutic agents and has as an object to provide improved compounds having tumour growth inhibitory action. The present application is a continuation in part of application Serial No. 413,724, filed March 2, 1954, now abandoned.

Bis-chloroethylamines of the general formula RN(-CH CH Cl) (I) in which R is hydrogen or a methyl or ethyl radical and n is an integer of from 1 to 4.

All the compounds of the general formula wmcmonmQowmnoo on where n is 1, 2, 3 or 4 are effective tumour growth inhibitors when tested against transplanted Walker rat carcinoma.

The compound of the formula:

(CHiCIEfiCDaNQ-O came 0 on i.e. p N,N di (2 chloroethyl) aminophenoxypropionic acid, has particularly good tumour growth inhibi tory action.

The present invention includes a process for the manufacture of compounds of the general Formula II above wherein a compound of the general formula:

in which R" is selected from the group consisting of methyl and ethyl radicals and n is an integer of from 1 to 4 is treated with phosphorus oxychloride to form a compound of the general formula:

(CHzOHaCDzN-Q-O can no 0 o a" which, if desired, is converted by hydrolysis in an acid medium into a compound of the general formula:

(omcmomm-Qmornnooon (II) I 3,105,847 Patented Oct. 1, 1963 The following examples, in which the parts are by weight, illustrate the invention: 7

EXAMPLE 1 p-N,N-Di-(2-Chloroethyl) -Aminophenoxyacetic Acid Ethyl p-aminophenoxyacetate (19 parts), ethylene oxide (210 parts), N-acetic acid (25 parts) were stirred at room temperature for four hours, then allowed to stand overnight. The resulting ethyl p-N,N-di-2-hydroxyethyl aminophenoxyacetate (4 parts), phosphorus oxychloride (5 parts) and chloroform (25 parts) were heated under reflux for one hour. Hydrolysis of the ethyl p-N,N-di-(2- chloroethyl)-aminophenoxyacetate (1 part) with concentrated hydrochloric acid (5 parts) was achieved by refluxing for thirty minutes. Neutralization with ammonia and extraction with ether gave p-N,-N-di-(2-chloroethyl)- aminophenoxyaoetic acid which was recrystallized from benzene/light petroleum, 60-80 0., MP. 105 C.

EXAMPLE 2 p-N,N-Di(2-Chloroethyl) -Aminophen0xypropi0fiic Acid Methyl p-aminophenoxypropionate (7 parts), ethylene oxide (10 parts) and N-acetic acid (25 parts) was stirred at room temperature for four hours and allowed to stand overnight. Removal of ethylene oxide and extraction with chloroform gave methyl p-N,N-di-2-hydroxyethylaminophenoxypropionate, which on recrystallization from benzene had a melting point of 68 C. in a yield of 7 parts. Chlorination of this compound (7 parts) with phosphorus oxychloride (7 parts) and benzene (50 parts) gave, after one hours refluxing, methyl p-N.N-di-(2- chloroethyl)-aminophenoxypropionate which was recrystallized from benzene and had a melting point of 51 C. This was hydrolyzed, using an equal amount of concentrated hydrochloric acid, to give p-N,N-di-(2-chloroethyl)-aminophenoxypropionic acid which wasrecrystallized from cyclohexane and had a melting point of 93 C.

EXAMPLE 3 p-N,N-Di-(2-Chl0r0ethyl) -Amin0phen0xybutyric Acid Methyl p-aminophenoxybutyrate (10 parts), ethylene oxide (20 parts) and N-acetic acid (25 parts) were stirred for four hours. Removal of ethylene oxide and extraction with chloroform gave methyl p-N,N-di-2-hydroxyethylaminop'henoxybutyrate which was recrystallized from benzene/cyclohexane and had a melting point of 57 C. This compound (5 parts), phosphorus oxychloride (5 parts) and benzene (40 parts) were refluxed together for an hour to give methyl p-N,N-di-(2-chloroethyl)-aminophenoxybutyrate which recrystallized from carbon tetrachloride/light petroleum, 40-60 C.,and had a melting point of C. Hydrolysis of this methyl ester (2 parts) with concentrated hydrochloric acid (2 parts) gave p- N,N-di-(2-ch-loroethyl)-aminophenoxybutyric acid which was recrystallized from cyclohexane and had a melting point of 855 C.

Experiments were carried out which showed the inhibition of the Walker rat carcinoma by the compounds of the present invention.

In each case transplanted Walker rat carcinoma was used employing the technique described by Badger, Elson, Haddow, Hewett and Robinson (Proc. Roy. Soc., 1942, B 130, 255) and Haddow, Harris, K011 and Roe (Phil. Trans. Roy. Soc., 1948, A 241, 147). In each experiment 10 rats were treated with a single dose of a compound of the invention and ten other rats were used as controls. The tumours were not always weighed in all drogen, methyl and ethyl radicals and n is an integer of the controls as some tumours in the controls were used as from 1 to 4.

initial materials for further experiments. 21 p N,N di (2 chloroethyl) aminophenoxypro- The results are shown in the following table: pionic acid.

Weight of tumour in gms. Compound Dose, Duration,

mg. days Controls Treated Ethyl p-(di-Z-chloroethyl) aminophenoxy acetate.-- 5 14, 40, 35, 34, 33, 33, 4, 4, 1. N0 tn- 27, 16, moms in the remaining seven animals p-(Dl-Z-ehloroethyl) aminophenoxyacetic acid 3 14 24, 23, 15, 11, 6, 3, N o tumours in any 3. of the animals. p-(D1-2chloroethyl) aminophenoxyproplonic aeitL- 1 14 24, 23, 15, 11. 6, 3, No tumours in any 3, 3. of the animals.

One animal died. p-(Di-2-chloroethyl) aminophenoxybutyrlc acid 1 14 35, 23,19, 18, 16, No tumours in any 14, 12, 8, 6. of the animals. p-(Dl-Z-ehloroethyl) aminophenoxy'valerie acid.-- 2 15 23,16,16, 8, 3, 3, 2 1, 0.5. No tumours No tumours in in the other two of the eight animals. animals. I

We claim: 7 References Cited in the file of this patent l. A compound of the formula: FOREIGN PATENTS r 128,912 Great Britain Oct. 30, 1919 tontonionm- -o oni .eoon' 25 738,415 Great Britain Oct. 12, 1955 7 OTHER REFERENCES in which R is selected from the group consisting of hy- Everett at 211.: Chem. Abstn, 44, 1431-2 (1950). 

1. A COMPOUND OF THE FORMULA: 